JP2022058482A - 生体内での存続性及び治療活性及びその増殖のためのnkt細胞サブセット - Google Patents
生体内での存続性及び治療活性及びその増殖のためのnkt細胞サブセット Download PDFInfo
- Publication number
- JP2022058482A JP2022058482A JP2022000207A JP2022000207A JP2022058482A JP 2022058482 A JP2022058482 A JP 2022058482A JP 2022000207 A JP2022000207 A JP 2022000207A JP 2022000207 A JP2022000207 A JP 2022000207A JP 2022058482 A JP2022058482 A JP 2022058482A
- Authority
- JP
- Japan
- Prior art keywords
- cells
- nkt
- cd62l
- nkt cells
- cell
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 238000001727 in vivo Methods 0.000 title description 24
- 230000001225 therapeutic effect Effects 0.000 title description 20
- 230000002688 persistence Effects 0.000 title description 2
- 210000000581 natural killer T-cell Anatomy 0.000 claims abstract description 174
- 101001018097 Homo sapiens L-selectin Proteins 0.000 claims abstract description 173
- 102100033467 L-selectin Human genes 0.000 claims abstract description 173
- 230000014509 gene expression Effects 0.000 claims abstract description 104
- 238000000034 method Methods 0.000 claims abstract description 73
- 108010019670 Chimeric Antigen Receptors Proteins 0.000 claims abstract description 60
- 239000000203 mixture Substances 0.000 claims abstract description 28
- 238000009169 immunotherapy Methods 0.000 claims abstract description 20
- 210000004027 cell Anatomy 0.000 claims description 227
- 206010028980 Neoplasm Diseases 0.000 claims description 68
- 230000000638 stimulation Effects 0.000 claims description 50
- 201000011510 cancer Diseases 0.000 claims description 47
- 239000000427 antigen Substances 0.000 claims description 44
- 108091007433 antigens Proteins 0.000 claims description 44
- 102000036639 antigens Human genes 0.000 claims description 44
- 108091008034 costimulatory receptors Proteins 0.000 claims description 32
- 239000003446 ligand Substances 0.000 claims description 24
- 102000004127 Cytokines Human genes 0.000 claims description 23
- 108090000695 Cytokines Proteins 0.000 claims description 23
- 101000851370 Homo sapiens Tumor necrosis factor receptor superfamily member 9 Proteins 0.000 claims description 23
- 102100036856 Tumor necrosis factor receptor superfamily member 9 Human genes 0.000 claims description 23
- 210000000612 antigen-presenting cell Anatomy 0.000 claims description 21
- 101000914514 Homo sapiens T-cell-specific surface glycoprotein CD28 Proteins 0.000 claims description 18
- 108010002350 Interleukin-2 Proteins 0.000 claims description 18
- 102000000588 Interleukin-2 Human genes 0.000 claims description 18
- 102100027213 T-cell-specific surface glycoprotein CD28 Human genes 0.000 claims description 18
- 102100022153 Tumor necrosis factor receptor superfamily member 4 Human genes 0.000 claims description 18
- 239000000556 agonist Substances 0.000 claims description 18
- 230000000694 effects Effects 0.000 claims description 18
- 101710165473 Tumor necrosis factor receptor superfamily member 4 Proteins 0.000 claims description 17
- 108010074108 interleukin-21 Proteins 0.000 claims description 15
- -1 OKT3mAb Chemical class 0.000 claims description 14
- 102000016266 T-Cell Antigen Receptors Human genes 0.000 claims description 14
- 238000010353 genetic engineering Methods 0.000 claims description 14
- 238000011282 treatment Methods 0.000 claims description 14
- 239000000758 substrate Substances 0.000 claims description 13
- 108091008874 T cell receptors Proteins 0.000 claims description 12
- 102000040430 polynucleotide Human genes 0.000 claims description 12
- 108091033319 polynucleotide Proteins 0.000 claims description 12
- 239000002157 polynucleotide Substances 0.000 claims description 12
- 102000005962 receptors Human genes 0.000 claims description 11
- 108020003175 receptors Proteins 0.000 claims description 11
- 230000002062 proliferating effect Effects 0.000 claims description 9
- 102100027207 CD27 antigen Human genes 0.000 claims description 8
- 101000914511 Homo sapiens CD27 antigen Proteins 0.000 claims description 8
- 238000004519 manufacturing process Methods 0.000 claims description 8
- 230000008685 targeting Effects 0.000 claims description 7
- 108010082808 4-1BB Ligand Proteins 0.000 claims description 6
- 108010042215 OX40 Ligand Proteins 0.000 claims description 6
- 102100026890 Tumor necrosis factor ligand superfamily member 4 Human genes 0.000 claims description 6
- 102100032101 Tumor necrosis factor ligand superfamily member 9 Human genes 0.000 claims description 6
- 239000011324 bead Substances 0.000 claims description 6
- VQFKFAKEUMHBLV-BYSUZVQFSA-N 1-O-(alpha-D-galactosyl)-N-hexacosanoylphytosphingosine Chemical compound CCCCCCCCCCCCCCCCCCCCCCCCCC(=O)N[C@H]([C@H](O)[C@H](O)CCCCCCCCCCCCCC)CO[C@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O VQFKFAKEUMHBLV-BYSUZVQFSA-N 0.000 claims description 5
- 229930186217 Glycolipid Natural products 0.000 claims description 5
- 101000851376 Homo sapiens Tumor necrosis factor receptor superfamily member 8 Proteins 0.000 claims description 5
- 108090000172 Interleukin-15 Proteins 0.000 claims description 5
- 102000003812 Interleukin-15 Human genes 0.000 claims description 5
- 102100036857 Tumor necrosis factor receptor superfamily member 8 Human genes 0.000 claims description 5
- 102000003675 cytokine receptors Human genes 0.000 claims description 5
- 108010057085 cytokine receptors Proteins 0.000 claims description 5
- 108010002586 Interleukin-7 Proteins 0.000 claims description 4
- 102100021592 Interleukin-7 Human genes 0.000 claims description 4
- 101000914484 Homo sapiens T-lymphocyte activation antigen CD80 Proteins 0.000 claims description 3
- 101100207070 Homo sapiens TNFSF8 gene Proteins 0.000 claims description 3
- 102100034980 ICOS ligand Human genes 0.000 claims description 3
- 101100207071 Mus musculus Tnfsf8 gene Proteins 0.000 claims description 3
- 102100027222 T-lymphocyte activation antigen CD80 Human genes 0.000 claims description 3
- 102100032100 Tumor necrosis factor ligand superfamily member 8 Human genes 0.000 claims description 3
- 239000012141 concentrate Substances 0.000 claims description 3
- 230000004936 stimulating effect Effects 0.000 claims description 3
- 101150013553 CD40 gene Proteins 0.000 claims description 2
- 102100032937 CD40 ligand Human genes 0.000 claims description 2
- 101000868215 Homo sapiens CD40 ligand Proteins 0.000 claims description 2
- 101710093458 ICOS ligand Proteins 0.000 claims description 2
- 102000013462 Interleukin-12 Human genes 0.000 claims description 2
- 108010065805 Interleukin-12 Proteins 0.000 claims description 2
- 108060008682 Tumor Necrosis Factor Proteins 0.000 claims description 2
- 102000000852 Tumor Necrosis Factor-alpha Human genes 0.000 claims description 2
- 102100040245 Tumor necrosis factor receptor superfamily member 5 Human genes 0.000 claims description 2
- 150000002334 glycols Chemical class 0.000 claims description 2
- 150000002632 lipids Chemical class 0.000 claims description 2
- HVCOBJNICQPDBP-UHFFFAOYSA-N 3-[3-[3,5-dihydroxy-6-methyl-4-(3,4,5-trihydroxy-6-methyloxan-2-yl)oxyoxan-2-yl]oxydecanoyloxy]decanoic acid;hydrate Chemical compound O.OC1C(OC(CC(=O)OC(CCCCCCC)CC(O)=O)CCCCCCC)OC(C)C(O)C1OC1C(O)C(O)C(O)C(C)O1 HVCOBJNICQPDBP-UHFFFAOYSA-N 0.000 claims 2
- 239000003795 chemical substances by application Substances 0.000 abstract description 2
- 230000000139 costimulatory effect Effects 0.000 abstract description 2
- 239000013598 vector Substances 0.000 description 59
- 150000007523 nucleic acids Chemical group 0.000 description 40
- 230000035755 proliferation Effects 0.000 description 38
- 238000000338 in vitro Methods 0.000 description 30
- 102000039446 nucleic acids Human genes 0.000 description 29
- 108020004707 nucleic acids Proteins 0.000 description 29
- 101000716102 Homo sapiens T-cell surface glycoprotein CD4 Proteins 0.000 description 25
- 102100036011 T-cell surface glycoprotein CD4 Human genes 0.000 description 25
- 108090000623 proteins and genes Proteins 0.000 description 24
- 102100024222 B-lymphocyte antigen CD19 Human genes 0.000 description 19
- 101000980825 Homo sapiens B-lymphocyte antigen CD19 Proteins 0.000 description 19
- 201000010099 disease Diseases 0.000 description 19
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 19
- 210000003819 peripheral blood mononuclear cell Anatomy 0.000 description 16
- 210000001744 T-lymphocyte Anatomy 0.000 description 15
- 239000008194 pharmaceutical composition Substances 0.000 description 14
- 241000699670 Mus sp. Species 0.000 description 13
- 230000001105 regulatory effect Effects 0.000 description 13
- 230000004083 survival effect Effects 0.000 description 13
- 241001465754 Metazoa Species 0.000 description 12
- 108091028043 Nucleic acid sequence Proteins 0.000 description 12
- 239000012636 effector Substances 0.000 description 12
- 238000001943 fluorescence-activated cell sorting Methods 0.000 description 12
- 210000005259 peripheral blood Anatomy 0.000 description 12
- 239000011886 peripheral blood Substances 0.000 description 12
- 230000035899 viability Effects 0.000 description 12
- 239000013604 expression vector Substances 0.000 description 11
- 238000010586 diagram Methods 0.000 description 10
- 210000004700 fetal blood Anatomy 0.000 description 10
- 239000000047 product Substances 0.000 description 10
- 230000004044 response Effects 0.000 description 10
- 238000004458 analytical method Methods 0.000 description 9
- 239000003153 chemical reaction reagent Substances 0.000 description 9
- 230000003013 cytotoxicity Effects 0.000 description 9
- 231100000135 cytotoxicity Toxicity 0.000 description 9
- 238000002347 injection Methods 0.000 description 9
- 239000007924 injection Substances 0.000 description 9
- 230000003834 intracellular effect Effects 0.000 description 9
- 238000012423 maintenance Methods 0.000 description 9
- 108090000765 processed proteins & peptides Proteins 0.000 description 9
- 108091026890 Coding region Proteins 0.000 description 8
- 108060001084 Luciferase Proteins 0.000 description 8
- 206010025323 Lymphomas Diseases 0.000 description 8
- 241000700605 Viruses Species 0.000 description 8
- 230000004069 differentiation Effects 0.000 description 8
- 239000003814 drug Substances 0.000 description 8
- 230000006870 function Effects 0.000 description 8
- 241001430294 unidentified retrovirus Species 0.000 description 8
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 7
- 108020004414 DNA Proteins 0.000 description 7
- 101000819111 Homo sapiens Trans-acting T-cell-specific transcription factor GATA-3 Proteins 0.000 description 7
- 239000005089 Luciferase Substances 0.000 description 7
- 102100027347 Neural cell adhesion molecule 1 Human genes 0.000 description 7
- 102100021386 Trans-acting T-cell-specific transcription factor GATA-3 Human genes 0.000 description 7
- 230000004913 activation Effects 0.000 description 7
- 230000000259 anti-tumor effect Effects 0.000 description 7
- 238000000684 flow cytometry Methods 0.000 description 7
- 239000002609 medium Substances 0.000 description 7
- 239000013612 plasmid Substances 0.000 description 7
- 102000004196 processed proteins & peptides Human genes 0.000 description 7
- 239000006228 supernatant Substances 0.000 description 7
- 101000581981 Homo sapiens Neural cell adhesion molecule 1 Proteins 0.000 description 6
- 101000622137 Homo sapiens P-selectin Proteins 0.000 description 6
- 102100023472 P-selectin Human genes 0.000 description 6
- 102000051792 Promyelocytic Leukemia Zinc Finger Human genes 0.000 description 6
- 108700003766 Promyelocytic Leukemia Zinc Finger Proteins 0.000 description 6
- 238000003556 assay Methods 0.000 description 6
- 230000004663 cell proliferation Effects 0.000 description 6
- 239000003623 enhancer Substances 0.000 description 6
- 210000003527 eukaryotic cell Anatomy 0.000 description 6
- 238000002474 experimental method Methods 0.000 description 6
- 238000003384 imaging method Methods 0.000 description 6
- 239000004615 ingredient Substances 0.000 description 6
- 229920001184 polypeptide Polymers 0.000 description 6
- 210000001236 prokaryotic cell Anatomy 0.000 description 6
- 102000004169 proteins and genes Human genes 0.000 description 6
- 102100034458 Hepatitis A virus cellular receptor 2 Human genes 0.000 description 5
- 101001049181 Homo sapiens Killer cell lectin-like receptor subfamily B member 1 Proteins 0.000 description 5
- 102100023678 Killer cell lectin-like receptor subfamily B member 1 Human genes 0.000 description 5
- 241000699666 Mus <mouse, genus> Species 0.000 description 5
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 5
- 238000009825 accumulation Methods 0.000 description 5
- 238000002659 cell therapy Methods 0.000 description 5
- 230000000875 corresponding effect Effects 0.000 description 5
- 229940079593 drug Drugs 0.000 description 5
- 230000012010 growth Effects 0.000 description 5
- 230000001965 increasing effect Effects 0.000 description 5
- 239000003550 marker Substances 0.000 description 5
- 210000003071 memory t lymphocyte Anatomy 0.000 description 5
- 125000003729 nucleotide group Chemical group 0.000 description 5
- 230000011664 signaling Effects 0.000 description 5
- 208000024891 symptom Diseases 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- 238000013518 transcription Methods 0.000 description 5
- 230000035897 transcription Effects 0.000 description 5
- 102100036301 C-C chemokine receptor type 7 Human genes 0.000 description 4
- 101710083479 Hepatitis A virus cellular receptor 2 homolog Proteins 0.000 description 4
- 101000716065 Homo sapiens C-C chemokine receptor type 7 Proteins 0.000 description 4
- 108090000978 Interleukin-4 Proteins 0.000 description 4
- 102000017578 LAG3 Human genes 0.000 description 4
- 101150030213 Lag3 gene Proteins 0.000 description 4
- 229940126547 T-cell immunoglobulin mucin-3 Drugs 0.000 description 4
- 108091023040 Transcription factor Proteins 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- 230000029918 bioluminescence Effects 0.000 description 4
- 238000005415 bioluminescence Methods 0.000 description 4
- 150000001875 compounds Chemical class 0.000 description 4
- 230000001472 cytotoxic effect Effects 0.000 description 4
- 238000011161 development Methods 0.000 description 4
- 230000018109 developmental process Effects 0.000 description 4
- 239000003937 drug carrier Substances 0.000 description 4
- 239000000839 emulsion Substances 0.000 description 4
- 230000001976 improved effect Effects 0.000 description 4
- 238000001990 intravenous administration Methods 0.000 description 4
- 210000004698 lymphocyte Anatomy 0.000 description 4
- 210000000822 natural killer cell Anatomy 0.000 description 4
- 230000001613 neoplastic effect Effects 0.000 description 4
- 239000002773 nucleotide Substances 0.000 description 4
- 210000000130 stem cell Anatomy 0.000 description 4
- 210000001519 tissue Anatomy 0.000 description 4
- 238000001890 transfection Methods 0.000 description 4
- 239000013603 viral vector Substances 0.000 description 4
- 102100034540 Adenomatous polyposis coli protein Human genes 0.000 description 3
- 108090000672 Annexin A5 Proteins 0.000 description 3
- 102000004121 Annexin A5 Human genes 0.000 description 3
- 102100024423 Carbonic anhydrase 9 Human genes 0.000 description 3
- 238000012413 Fluorescence activated cell sorting analysis Methods 0.000 description 3
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 3
- 241000124008 Mammalia Species 0.000 description 3
- 101100094860 Mus musculus Slc22a6 gene Proteins 0.000 description 3
- 206010029260 Neuroblastoma Diseases 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 102000040945 Transcription factor Human genes 0.000 description 3
- GLNADSQYFUSGOU-GPTZEZBUSA-J Trypan blue Chemical compound [Na+].[Na+].[Na+].[Na+].C1=C(S([O-])(=O)=O)C=C2C=C(S([O-])(=O)=O)C(/N=N/C3=CC=C(C=C3C)C=3C=C(C(=CC=3)\N=N\C=3C(=CC4=CC(=CC(N)=C4C=3O)S([O-])(=O)=O)S([O-])(=O)=O)C)=C(O)C2=C1N GLNADSQYFUSGOU-GPTZEZBUSA-J 0.000 description 3
- 230000006907 apoptotic process Effects 0.000 description 3
- 238000013459 approach Methods 0.000 description 3
- 238000002619 cancer immunotherapy Methods 0.000 description 3
- 230000001413 cellular effect Effects 0.000 description 3
- 238000010367 cloning Methods 0.000 description 3
- 238000011260 co-administration Methods 0.000 description 3
- 230000004186 co-expression Effects 0.000 description 3
- 231100000433 cytotoxic Toxicity 0.000 description 3
- 230000001419 dependent effect Effects 0.000 description 3
- 239000008121 dextrose Substances 0.000 description 3
- 238000010790 dilution Methods 0.000 description 3
- 239000012895 dilution Substances 0.000 description 3
- 239000012634 fragment Substances 0.000 description 3
- 238000001415 gene therapy Methods 0.000 description 3
- 239000002502 liposome Substances 0.000 description 3
- 230000007774 longterm Effects 0.000 description 3
- 230000014759 maintenance of location Effects 0.000 description 3
- 230000007246 mechanism Effects 0.000 description 3
- 108020004999 messenger RNA Proteins 0.000 description 3
- 238000011275 oncology therapy Methods 0.000 description 3
- 238000001543 one-way ANOVA Methods 0.000 description 3
- 238000007427 paired t-test Methods 0.000 description 3
- 230000002093 peripheral effect Effects 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 230000002265 prevention Effects 0.000 description 3
- 230000008569 process Effects 0.000 description 3
- 239000011780 sodium chloride Substances 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 238000010186 staining Methods 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 238000010361 transduction Methods 0.000 description 3
- 230000026683 transduction Effects 0.000 description 3
- 210000004881 tumor cell Anatomy 0.000 description 3
- 230000004614 tumor growth Effects 0.000 description 3
- 241000701161 unidentified adenovirus Species 0.000 description 3
- 241001529453 unidentified herpesvirus Species 0.000 description 3
- 230000003827 upregulation Effects 0.000 description 3
- 230000003612 virological effect Effects 0.000 description 3
- 108700012813 7-aminoactinomycin D Proteins 0.000 description 2
- YXHLJMWYDTXDHS-IRFLANFNSA-N 7-aminoactinomycin D Chemical compound C[C@H]1OC(=O)[C@H](C(C)C)N(C)C(=O)CN(C)C(=O)[C@@H]2CCCN2C(=O)[C@@H](C(C)C)NC(=O)[C@H]1NC(=O)C1=C(N)C(=O)C(C)=C2OC(C(C)=C(N)C=C3C(=O)N[C@@H]4C(=O)N[C@@H](C(N5CCC[C@H]5C(=O)N(C)CC(=O)N(C)[C@@H](C(C)C)C(=O)O[C@@H]4C)=O)C(C)C)=C3N=C21 YXHLJMWYDTXDHS-IRFLANFNSA-N 0.000 description 2
- 102100038080 B-cell receptor CD22 Human genes 0.000 description 2
- 206010006187 Breast cancer Diseases 0.000 description 2
- 208000026310 Breast neoplasm Diseases 0.000 description 2
- 229940122738 CD3 agonist Drugs 0.000 description 2
- 108010058905 CD44v6 antigen Proteins 0.000 description 2
- 102100025475 Carcinoembryonic antigen-related cell adhesion molecule 5 Human genes 0.000 description 2
- 206010008342 Cervix carcinoma Diseases 0.000 description 2
- 102100028757 Chondroitin sulfate proteoglycan 4 Human genes 0.000 description 2
- 241000282412 Homo Species 0.000 description 2
- 101000884305 Homo sapiens B-cell receptor CD22 Proteins 0.000 description 2
- 101000916489 Homo sapiens Chondroitin sulfate proteoglycan 4 Proteins 0.000 description 2
- 101001109501 Homo sapiens NKG2-D type II integral membrane protein Proteins 0.000 description 2
- 101001012157 Homo sapiens Receptor tyrosine-protein kinase erbB-2 Proteins 0.000 description 2
- 108060003951 Immunoglobulin Proteins 0.000 description 2
- 102100030703 Interleukin-22 Human genes 0.000 description 2
- 102100036672 Interleukin-23 receptor Human genes 0.000 description 2
- 102100022680 NKG2-D type II integral membrane protein Human genes 0.000 description 2
- 229930193140 Neomycin Natural products 0.000 description 2
- 206010061309 Neoplasm progression Diseases 0.000 description 2
- 102000052812 Ornithine decarboxylases Human genes 0.000 description 2
- 108700005126 Ornithine decarboxylases Proteins 0.000 description 2
- 108091093037 Peptide nucleic acid Proteins 0.000 description 2
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 2
- 102100030086 Receptor tyrosine-protein kinase erbB-2 Human genes 0.000 description 2
- 239000006146 Roswell Park Memorial Institute medium Substances 0.000 description 2
- 208000003837 Second Primary Neoplasms Diseases 0.000 description 2
- 238000000692 Student's t-test Methods 0.000 description 2
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 description 2
- 230000000735 allogeneic effect Effects 0.000 description 2
- 230000001640 apoptogenic effect Effects 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 2
- 239000000872 buffer Substances 0.000 description 2
- 238000004113 cell culture Methods 0.000 description 2
- 230000011748 cell maturation Effects 0.000 description 2
- 201000010881 cervical cancer Diseases 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 238000002512 chemotherapy Methods 0.000 description 2
- 108700010039 chimeric receptor Proteins 0.000 description 2
- 210000001228 classical NK T cell Anatomy 0.000 description 2
- 208000029742 colonic neoplasm Diseases 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- 230000016396 cytokine production Effects 0.000 description 2
- 230000001086 cytosolic effect Effects 0.000 description 2
- 230000003828 downregulation Effects 0.000 description 2
- VLCYCQAOQCDTCN-UHFFFAOYSA-N eflornithine Chemical compound NCCCC(N)(C(F)F)C(O)=O VLCYCQAOQCDTCN-UHFFFAOYSA-N 0.000 description 2
- 238000004520 electroporation Methods 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 230000002708 enhancing effect Effects 0.000 description 2
- 230000007717 exclusion Effects 0.000 description 2
- OVBPIULPVIDEAO-LBPRGKRZSA-N folic acid Chemical compound C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 OVBPIULPVIDEAO-LBPRGKRZSA-N 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 239000000499 gel Substances 0.000 description 2
- 238000001794 hormone therapy Methods 0.000 description 2
- 210000002865 immune cell Anatomy 0.000 description 2
- 102000018358 immunoglobulin Human genes 0.000 description 2
- 230000000415 inactivating effect Effects 0.000 description 2
- 230000010354 integration Effects 0.000 description 2
- 108040001844 interleukin-23 receptor activity proteins Proteins 0.000 description 2
- 230000002147 killing effect Effects 0.000 description 2
- 208000020816 lung neoplasm Diseases 0.000 description 2
- 230000001404 mediated effect Effects 0.000 description 2
- 201000001441 melanoma Diseases 0.000 description 2
- 239000011325 microbead Substances 0.000 description 2
- 238000010172 mouse model Methods 0.000 description 2
- 230000035772 mutation Effects 0.000 description 2
- 229960004927 neomycin Drugs 0.000 description 2
- 230000002085 persistent effect Effects 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- 230000010287 polarization Effects 0.000 description 2
- 230000023603 positive regulation of transcription initiation, DNA-dependent Effects 0.000 description 2
- 230000029279 positive regulation of transcription, DNA-dependent Effects 0.000 description 2
- 230000003389 potentiating effect Effects 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 230000000284 resting effect Effects 0.000 description 2
- 230000000717 retained effect Effects 0.000 description 2
- 108010056030 retronectin Proteins 0.000 description 2
- 230000001177 retroviral effect Effects 0.000 description 2
- 238000012216 screening Methods 0.000 description 2
- 230000028327 secretion Effects 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 125000006850 spacer group Chemical group 0.000 description 2
- 230000006641 stabilisation Effects 0.000 description 2
- 238000011105 stabilization Methods 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 238000012353 t test Methods 0.000 description 2
- 238000013519 translation Methods 0.000 description 2
- 230000005751 tumor progression Effects 0.000 description 2
- 241001515965 unidentified phage Species 0.000 description 2
- 239000003981 vehicle Substances 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- 102100031585 ADP-ribosyl cyclase/cyclic ADP-ribose hydrolase 1 Human genes 0.000 description 1
- HJCMDXDYPOUFDY-WHFBIAKZSA-N Ala-Gln Chemical compound C[C@H](N)C(=O)N[C@H](C(O)=O)CCC(N)=O HJCMDXDYPOUFDY-WHFBIAKZSA-N 0.000 description 1
- 102100036826 Aldehyde oxidase Human genes 0.000 description 1
- 208000023275 Autoimmune disease Diseases 0.000 description 1
- 208000003950 B-cell lymphoma Diseases 0.000 description 1
- 102100022005 B-lymphocyte antigen CD20 Human genes 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- 102100021663 Baculoviral IAP repeat-containing protein 5 Human genes 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 1
- 241000701822 Bovine papillomavirus Species 0.000 description 1
- 108700012439 CA9 Proteins 0.000 description 1
- 108700013048 CCL2 Proteins 0.000 description 1
- 229940123205 CD28 agonist Drugs 0.000 description 1
- 101150100936 CD28 gene Proteins 0.000 description 1
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 1
- 102100025570 Cancer/testis antigen 1 Human genes 0.000 description 1
- 241000282472 Canis lupus familiaris Species 0.000 description 1
- 241000283707 Capra Species 0.000 description 1
- 108010022366 Carcinoembryonic Antigen Proteins 0.000 description 1
- 201000009030 Carcinoma Diseases 0.000 description 1
- 102100026550 Caspase-9 Human genes 0.000 description 1
- 108090000566 Caspase-9 Proteins 0.000 description 1
- 102000000018 Chemokine CCL2 Human genes 0.000 description 1
- 102000019034 Chemokines Human genes 0.000 description 1
- 108010012236 Chemokines Proteins 0.000 description 1
- 108091007741 Chimeric antigen receptor T cells Proteins 0.000 description 1
- 244000205754 Colocasia esculenta Species 0.000 description 1
- 235000006481 Colocasia esculenta Nutrition 0.000 description 1
- 206010009944 Colon cancer Diseases 0.000 description 1
- WQZGKKKJIJFFOK-QTVWNMPRSA-N D-mannopyranose Chemical compound OC[C@H]1OC(O)[C@@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-QTVWNMPRSA-N 0.000 description 1
- 101150074155 DHFR gene Proteins 0.000 description 1
- 238000001712 DNA sequencing Methods 0.000 description 1
- 241000702421 Dependoparvovirus Species 0.000 description 1
- 238000002965 ELISA Methods 0.000 description 1
- LVGKNOAMLMIIKO-UHFFFAOYSA-N Elaidinsaeure-aethylester Natural products CCCCCCCCC=CCCCCCCCC(=O)OCC LVGKNOAMLMIIKO-UHFFFAOYSA-N 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- 206010014733 Endometrial cancer Diseases 0.000 description 1
- 206010014759 Endometrial neoplasm Diseases 0.000 description 1
- 102000004533 Endonucleases Human genes 0.000 description 1
- 108010042407 Endonucleases Proteins 0.000 description 1
- YQYJSBFKSSDGFO-UHFFFAOYSA-N Epihygromycin Natural products OC1C(O)C(C(=O)C)OC1OC(C(=C1)O)=CC=C1C=C(C)C(=O)NC1C(O)C(O)C2OCOC2C1O YQYJSBFKSSDGFO-UHFFFAOYSA-N 0.000 description 1
- 102100031940 Epithelial cell adhesion molecule Human genes 0.000 description 1
- 241000283086 Equidae Species 0.000 description 1
- 241000588724 Escherichia coli Species 0.000 description 1
- 208000000461 Esophageal Neoplasms Diseases 0.000 description 1
- 241000206602 Eukaryota Species 0.000 description 1
- 108060002716 Exonuclease Proteins 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- 108090000331 Firefly luciferases Proteins 0.000 description 1
- 101150094690 GAL1 gene Proteins 0.000 description 1
- 108010003338 GATA3 Transcription Factor Proteins 0.000 description 1
- 102000004610 GATA3 Transcription Factor Human genes 0.000 description 1
- 101150060333 GATA3 gene Proteins 0.000 description 1
- 102100028501 Galanin peptides Human genes 0.000 description 1
- 102000053187 Glucuronidase Human genes 0.000 description 1
- 108010060309 Glucuronidase Proteins 0.000 description 1
- 102100041003 Glutamate carboxypeptidase 2 Human genes 0.000 description 1
- 102100032530 Glypican-3 Human genes 0.000 description 1
- 102000004269 Granulocyte Colony-Stimulating Factor Human genes 0.000 description 1
- 108010017080 Granulocyte Colony-Stimulating Factor Proteins 0.000 description 1
- 108010043121 Green Fluorescent Proteins Proteins 0.000 description 1
- 102000004144 Green Fluorescent Proteins Human genes 0.000 description 1
- 102100028971 HLA class I histocompatibility antigen, C alpha chain Human genes 0.000 description 1
- 102000025850 HLA-A2 Antigen Human genes 0.000 description 1
- 108010074032 HLA-A2 Antigen Proteins 0.000 description 1
- 108010052199 HLA-C Antigens Proteins 0.000 description 1
- 102100034459 Hepatitis A virus cellular receptor 1 Human genes 0.000 description 1
- 108010088652 Histocompatibility Antigens Class I Proteins 0.000 description 1
- 102000008949 Histocompatibility Antigens Class I Human genes 0.000 description 1
- 101000777636 Homo sapiens ADP-ribosyl cyclase/cyclic ADP-ribose hydrolase 1 Proteins 0.000 description 1
- 101000928314 Homo sapiens Aldehyde oxidase Proteins 0.000 description 1
- 101000897405 Homo sapiens B-lymphocyte antigen CD20 Proteins 0.000 description 1
- 101000856237 Homo sapiens Cancer/testis antigen 1 Proteins 0.000 description 1
- 101000910338 Homo sapiens Carbonic anhydrase 9 Proteins 0.000 description 1
- 101000914324 Homo sapiens Carcinoembryonic antigen-related cell adhesion molecule 5 Proteins 0.000 description 1
- 101000914321 Homo sapiens Carcinoembryonic antigen-related cell adhesion molecule 7 Proteins 0.000 description 1
- 101000920667 Homo sapiens Epithelial cell adhesion molecule Proteins 0.000 description 1
- 101100121078 Homo sapiens GAL gene Proteins 0.000 description 1
- 101000892862 Homo sapiens Glutamate carboxypeptidase 2 Proteins 0.000 description 1
- 101001014668 Homo sapiens Glypican-3 Proteins 0.000 description 1
- 101001068136 Homo sapiens Hepatitis A virus cellular receptor 1 Proteins 0.000 description 1
- 101001068133 Homo sapiens Hepatitis A virus cellular receptor 2 Proteins 0.000 description 1
- 101001019455 Homo sapiens ICOS ligand Proteins 0.000 description 1
- 101001103039 Homo sapiens Inactive tyrosine-protein kinase transmembrane receptor ROR1 Proteins 0.000 description 1
- 101000599852 Homo sapiens Intercellular adhesion molecule 1 Proteins 0.000 description 1
- 101000998120 Homo sapiens Interleukin-3 receptor subunit alpha Proteins 0.000 description 1
- 101001133056 Homo sapiens Mucin-1 Proteins 0.000 description 1
- 101000623901 Homo sapiens Mucin-16 Proteins 0.000 description 1
- 101000934338 Homo sapiens Myeloid cell surface antigen CD33 Proteins 0.000 description 1
- 101000884270 Homo sapiens Natural killer cell receptor 2B4 Proteins 0.000 description 1
- 101001103036 Homo sapiens Nuclear receptor ROR-alpha Proteins 0.000 description 1
- 101000603882 Homo sapiens Nuclear receptor subfamily 1 group I member 3 Proteins 0.000 description 1
- 101000617725 Homo sapiens Pregnancy-specific beta-1-glycoprotein 2 Proteins 0.000 description 1
- 101000831286 Homo sapiens Protein timeless homolog Proteins 0.000 description 1
- 101001076732 Homo sapiens RNA-binding protein 27 Proteins 0.000 description 1
- 101000752245 Homo sapiens Rho guanine nucleotide exchange factor 5 Proteins 0.000 description 1
- 101000693265 Homo sapiens Sphingosine 1-phosphate receptor 1 Proteins 0.000 description 1
- 101000669511 Homo sapiens T-cell immunoglobulin and mucin domain-containing protein 4 Proteins 0.000 description 1
- 101000934346 Homo sapiens T-cell surface antigen CD2 Proteins 0.000 description 1
- 101000801234 Homo sapiens Tumor necrosis factor receptor superfamily member 18 Proteins 0.000 description 1
- 101000679851 Homo sapiens Tumor necrosis factor receptor superfamily member 4 Proteins 0.000 description 1
- 101150003028 Hprt1 gene Proteins 0.000 description 1
- 206010021143 Hypoxia Diseases 0.000 description 1
- 102100039615 Inactive tyrosine-protein kinase transmembrane receptor ROR1 Human genes 0.000 description 1
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 1
- 102100037877 Intercellular adhesion molecule 1 Human genes 0.000 description 1
- 102000004559 Interleukin-13 Receptors Human genes 0.000 description 1
- 108010017511 Interleukin-13 Receptors Proteins 0.000 description 1
- 102000004527 Interleukin-21 Receptors Human genes 0.000 description 1
- 108010017411 Interleukin-21 Receptors Proteins 0.000 description 1
- 102100033493 Interleukin-3 receptor subunit alpha Human genes 0.000 description 1
- 208000008839 Kidney Neoplasms Diseases 0.000 description 1
- FBOZXECLQNJBKD-ZDUSSCGKSA-N L-methotrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FBOZXECLQNJBKD-ZDUSSCGKSA-N 0.000 description 1
- QIVBCDIJIAJPQS-VIFPVBQESA-N L-tryptophane Chemical compound C1=CC=C2C(C[C@H](N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-VIFPVBQESA-N 0.000 description 1
- 241000713666 Lentivirus Species 0.000 description 1
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 1
- 108700012912 MYCN Proteins 0.000 description 1
- 101150022024 MYCN gene Proteins 0.000 description 1
- 108700018351 Major Histocompatibility Complex Proteins 0.000 description 1
- 108091022912 Mannose-6-Phosphate Isomerase Proteins 0.000 description 1
- 102000048193 Mannose-6-phosphate isomerases Human genes 0.000 description 1
- 108010061593 Member 14 Tumor Necrosis Factor Receptors Proteins 0.000 description 1
- 102000003735 Mesothelin Human genes 0.000 description 1
- 108090000015 Mesothelin Proteins 0.000 description 1
- 101100261636 Methanothermobacter marburgensis (strain ATCC BAA-927 / DSM 2133 / JCM 14651 / NBRC 100331 / OCM 82 / Marburg) trpB2 gene Proteins 0.000 description 1
- 241000713869 Moloney murine leukemia virus Species 0.000 description 1
- 102100034256 Mucin-1 Human genes 0.000 description 1
- 102100023123 Mucin-16 Human genes 0.000 description 1
- 101100341510 Mus musculus Itgal gene Proteins 0.000 description 1
- 101000597780 Mus musculus Tumor necrosis factor ligand superfamily member 18 Proteins 0.000 description 1
- 102100025243 Myeloid cell surface antigen CD33 Human genes 0.000 description 1
- 108700026495 N-Myc Proto-Oncogene Proteins 0.000 description 1
- OVBPIULPVIDEAO-UHFFFAOYSA-N N-Pteroyl-L-glutaminsaeure Natural products C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)NC(CCC(O)=O)C(O)=O)C=C1 OVBPIULPVIDEAO-UHFFFAOYSA-N 0.000 description 1
- 102100030124 N-myc proto-oncogene protein Human genes 0.000 description 1
- 102100038082 Natural killer cell receptor 2B4 Human genes 0.000 description 1
- 108010069196 Neural Cell Adhesion Molecules Proteins 0.000 description 1
- 238000000636 Northern blotting Methods 0.000 description 1
- 206010030155 Oesophageal carcinoma Diseases 0.000 description 1
- 229940122060 Ornithine decarboxylase inhibitor Drugs 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- 206010033128 Ovarian cancer Diseases 0.000 description 1
- 206010061535 Ovarian neoplasm Diseases 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 206010061902 Pancreatic neoplasm Diseases 0.000 description 1
- 241001494479 Pecora Species 0.000 description 1
- 101100124346 Photorhabdus laumondii subsp. laumondii (strain DSM 15139 / CIP 105565 / TT01) hisCD gene Proteins 0.000 description 1
- 239000004698 Polyethylene Substances 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 206010060862 Prostate cancer Diseases 0.000 description 1
- 108010076504 Protein Sorting Signals Proteins 0.000 description 1
- 102100025873 RNA-binding protein 27 Human genes 0.000 description 1
- 239000012980 RPMI-1640 medium Substances 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- 206010070308 Refractory cancer Diseases 0.000 description 1
- 206010038389 Renal cancer Diseases 0.000 description 1
- 208000007660 Residual Neoplasm Diseases 0.000 description 1
- 241000714474 Rous sarcoma virus Species 0.000 description 1
- 240000004808 Saccharomyces cerevisiae Species 0.000 description 1
- 208000004337 Salivary Gland Neoplasms Diseases 0.000 description 1
- 206010061934 Salivary gland cancer Diseases 0.000 description 1
- 108010071390 Serum Albumin Proteins 0.000 description 1
- 102000007562 Serum Albumin Human genes 0.000 description 1
- 208000000453 Skin Neoplasms Diseases 0.000 description 1
- 238000002105 Southern blotting Methods 0.000 description 1
- 102100025750 Sphingosine 1-phosphate receptor 1 Human genes 0.000 description 1
- 108091081024 Start codon Proteins 0.000 description 1
- 208000005718 Stomach Neoplasms Diseases 0.000 description 1
- 108010002687 Survivin Proteins 0.000 description 1
- 230000006052 T cell proliferation Effects 0.000 description 1
- 102100039367 T-cell immunoglobulin and mucin domain-containing protein 4 Human genes 0.000 description 1
- 102100025237 T-cell surface antigen CD2 Human genes 0.000 description 1
- 102000006601 Thymidine Kinase Human genes 0.000 description 1
- 108020004440 Thymidine kinase Proteins 0.000 description 1
- 208000024770 Thyroid neoplasm Diseases 0.000 description 1
- QIVBCDIJIAJPQS-UHFFFAOYSA-N Tryptophan Natural products C1=CC=C2C(CC(N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-UHFFFAOYSA-N 0.000 description 1
- 102100035283 Tumor necrosis factor ligand superfamily member 18 Human genes 0.000 description 1
- 102100028785 Tumor necrosis factor receptor superfamily member 14 Human genes 0.000 description 1
- 102100033728 Tumor necrosis factor receptor superfamily member 18 Human genes 0.000 description 1
- 241000700618 Vaccinia virus Species 0.000 description 1
- 108010019530 Vascular Endothelial Growth Factors Proteins 0.000 description 1
- 102000005789 Vascular Endothelial Growth Factors Human genes 0.000 description 1
- HMNZFMSWFCAGGW-XPWSMXQVSA-N [3-[hydroxy(2-hydroxyethoxy)phosphoryl]oxy-2-[(e)-octadec-9-enoyl]oxypropyl] (e)-octadec-9-enoate Chemical compound CCCCCCCC\C=C\CCCCCCCC(=O)OCC(COP(O)(=O)OCCO)OC(=O)CCCCCCC\C=C\CCCCCCCC HMNZFMSWFCAGGW-XPWSMXQVSA-N 0.000 description 1
- 230000005856 abnormality Effects 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 229940126575 aminoglycoside Drugs 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 230000006023 anti-tumor response Effects 0.000 description 1
- 230000030741 antigen processing and presentation Effects 0.000 description 1
- 230000000890 antigenic effect Effects 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 239000008365 aqueous carrier Substances 0.000 description 1
- 239000012736 aqueous medium Substances 0.000 description 1
- 239000003125 aqueous solvent Substances 0.000 description 1
- 210000001367 artery Anatomy 0.000 description 1
- 238000003149 assay kit Methods 0.000 description 1
- 230000003190 augmentative effect Effects 0.000 description 1
- 210000000941 bile Anatomy 0.000 description 1
- 210000000013 bile duct Anatomy 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000000481 breast Anatomy 0.000 description 1
- 239000001110 calcium chloride Substances 0.000 description 1
- 229910001628 calcium chloride Inorganic materials 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 229910000389 calcium phosphate Inorganic materials 0.000 description 1
- 235000011010 calcium phosphates Nutrition 0.000 description 1
- BPKIGYQJPYCAOW-FFJTTWKXSA-I calcium;potassium;disodium;(2s)-2-hydroxypropanoate;dichloride;dihydroxide;hydrate Chemical compound O.[OH-].[OH-].[Na+].[Na+].[Cl-].[Cl-].[K+].[Ca+2].C[C@H](O)C([O-])=O BPKIGYQJPYCAOW-FFJTTWKXSA-I 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 230000030833 cell death Effects 0.000 description 1
- 230000011712 cell development Effects 0.000 description 1
- 230000007248 cellular mechanism Effects 0.000 description 1
- 230000036755 cellular response Effects 0.000 description 1
- 239000002738 chelating agent Substances 0.000 description 1
- 239000013599 cloning vector Substances 0.000 description 1
- 238000012761 co-transfection Methods 0.000 description 1
- 238000002648 combination therapy Methods 0.000 description 1
- 238000004891 communication Methods 0.000 description 1
- 239000002299 complementary DNA Substances 0.000 description 1
- 230000002596 correlated effect Effects 0.000 description 1
- 229940127089 cytotoxic agent Drugs 0.000 description 1
- 238000002784 cytotoxicity assay Methods 0.000 description 1
- 231100000263 cytotoxicity test Toxicity 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 230000034994 death Effects 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 210000003317 double-positive, alpha-beta immature T lymphocyte Anatomy 0.000 description 1
- 238000009510 drug design Methods 0.000 description 1
- 238000002651 drug therapy Methods 0.000 description 1
- 230000009977 dual effect Effects 0.000 description 1
- 210000003162 effector t lymphocyte Anatomy 0.000 description 1
- 239000003792 electrolyte Substances 0.000 description 1
- 210000003386 epithelial cell of thymus gland Anatomy 0.000 description 1
- 230000008029 eradication Effects 0.000 description 1
- 201000004101 esophageal cancer Diseases 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- LVGKNOAMLMIIKO-QXMHVHEDSA-N ethyl oleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC LVGKNOAMLMIIKO-QXMHVHEDSA-N 0.000 description 1
- 229940093471 ethyl oleate Drugs 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 102000013165 exonuclease Human genes 0.000 description 1
- 238000010195 expression analysis Methods 0.000 description 1
- 239000012091 fetal bovine serum Substances 0.000 description 1
- 230000001605 fetal effect Effects 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 239000007850 fluorescent dye Substances 0.000 description 1
- 229960000304 folic acid Drugs 0.000 description 1
- 235000019152 folic acid Nutrition 0.000 description 1
- 239000011724 folic acid Substances 0.000 description 1
- 230000005714 functional activity Effects 0.000 description 1
- 230000004927 fusion Effects 0.000 description 1
- 108020001507 fusion proteins Proteins 0.000 description 1
- 102000037865 fusion proteins Human genes 0.000 description 1
- 108010027225 gag-pol Fusion Proteins Proteins 0.000 description 1
- 206010017758 gastric cancer Diseases 0.000 description 1
- 238000010363 gene targeting Methods 0.000 description 1
- 208000005017 glioblastoma Diseases 0.000 description 1
- 108060003196 globin Proteins 0.000 description 1
- 102000018146 globin Human genes 0.000 description 1
- 239000005090 green fluorescent protein Substances 0.000 description 1
- 230000003394 haemopoietic effect Effects 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 101150113423 hisD gene Proteins 0.000 description 1
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 description 1
- 230000001146 hypoxic effect Effects 0.000 description 1
- 102000027596 immune receptors Human genes 0.000 description 1
- 108091008915 immune receptors Proteins 0.000 description 1
- 230000008073 immune recognition Effects 0.000 description 1
- 230000036039 immunity Effects 0.000 description 1
- 238000002649 immunization Methods 0.000 description 1
- 230000003053 immunization Effects 0.000 description 1
- 229940072221 immunoglobulins Drugs 0.000 description 1
- 230000001771 impaired effect Effects 0.000 description 1
- 238000010348 incorporation Methods 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 239000011261 inert gas Substances 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 230000000977 initiatory effect Effects 0.000 description 1
- 210000004964 innate lymphoid cell Anatomy 0.000 description 1
- 238000003780 insertion Methods 0.000 description 1
- 230000037431 insertion Effects 0.000 description 1
- 230000024949 interleukin-17 production Effects 0.000 description 1
- 230000017307 interleukin-4 production Effects 0.000 description 1
- 238000001361 intraarterial administration Methods 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 238000005304 joining Methods 0.000 description 1
- 201000010982 kidney cancer Diseases 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 208000032839 leukemia Diseases 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 201000007270 liver cancer Diseases 0.000 description 1
- 208000014018 liver neoplasm Diseases 0.000 description 1
- 238000001325 log-rank test Methods 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 201000005202 lung cancer Diseases 0.000 description 1
- 210000002540 macrophage Anatomy 0.000 description 1
- 238000007885 magnetic separation Methods 0.000 description 1
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- 230000001394 metastastic effect Effects 0.000 description 1
- 208000037819 metastatic cancer Diseases 0.000 description 1
- 208000011575 metastatic malignant neoplasm Diseases 0.000 description 1
- 229960000485 methotrexate Drugs 0.000 description 1
- 230000000813 microbial effect Effects 0.000 description 1
- 230000000116 mitigating effect Effects 0.000 description 1
- 230000009456 molecular mechanism Effects 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 210000005087 mononuclear cell Anatomy 0.000 description 1
- 238000002703 mutagenesis Methods 0.000 description 1
- 231100000350 mutagenesis Toxicity 0.000 description 1
- 108700024542 myc Genes Proteins 0.000 description 1
- DDOVBCWVTOHGCU-QMXMISKISA-N n-[(e,2s,3r)-3-hydroxy-1-[(2r,3r,4s,5r,6r)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxynonadec-4-en-2-yl]octadecanamide Chemical compound CCCCCCCCCCCCCCCCCC(=O)N[C@H]([C@H](O)\C=C\CCCCCCCCCCCCCC)CO[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O DDOVBCWVTOHGCU-QMXMISKISA-N 0.000 description 1
- 239000013642 negative control Substances 0.000 description 1
- 239000012457 nonaqueous media Substances 0.000 description 1
- 239000000346 nonvolatile oil Substances 0.000 description 1
- 235000015097 nutrients Nutrition 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 235000019198 oils Nutrition 0.000 description 1
- 239000004006 olive oil Substances 0.000 description 1
- 235000008390 olive oil Nutrition 0.000 description 1
- 230000005868 ontogenesis Effects 0.000 description 1
- 150000002895 organic esters Chemical class 0.000 description 1
- 239000002818 ornithine decarboxylase inhibitor Substances 0.000 description 1
- 201000002528 pancreatic cancer Diseases 0.000 description 1
- 208000008443 pancreatic carcinoma Diseases 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 229920001481 poly(stearyl methacrylate) Polymers 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 238000003752 polymerase chain reaction Methods 0.000 description 1
- 230000002028 premature Effects 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 239000013615 primer Substances 0.000 description 1
- 239000002987 primer (paints) Substances 0.000 description 1
- 230000000750 progressive effect Effects 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 210000002307 prostate Anatomy 0.000 description 1
- 230000020978 protein processing Effects 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- 208000016691 refractory malignant neoplasm Diseases 0.000 description 1
- 230000008439 repair process Effects 0.000 description 1
- 230000010076 replication Effects 0.000 description 1
- 230000003362 replicative effect Effects 0.000 description 1
- 210000005000 reproductive tract Anatomy 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 230000003248 secreting effect Effects 0.000 description 1
- 230000019491 signal transduction Effects 0.000 description 1
- 201000000849 skin cancer Diseases 0.000 description 1
- 201000002314 small intestine cancer Diseases 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 230000000087 stabilizing effect Effects 0.000 description 1
- 239000008174 sterile solution Substances 0.000 description 1
- 201000011549 stomach cancer Diseases 0.000 description 1
- 230000020382 suppression by virus of host antigen processing and presentation of peptide antigen via MHC class I Effects 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 230000002195 synergetic effect Effects 0.000 description 1
- 101150047061 tag-72 gene Proteins 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 230000002992 thymic effect Effects 0.000 description 1
- 210000001541 thymus gland Anatomy 0.000 description 1
- 201000002510 thyroid cancer Diseases 0.000 description 1
- 239000003053 toxin Substances 0.000 description 1
- 231100000765 toxin Toxicity 0.000 description 1
- 108700012359 toxins Proteins 0.000 description 1
- 230000005026 transcription initiation Effects 0.000 description 1
- 230000005030 transcription termination Effects 0.000 description 1
- 230000002103 transcriptional effect Effects 0.000 description 1
- 238000012085 transcriptional profiling Methods 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 230000001131 transforming effect Effects 0.000 description 1
- 230000009261 transgenic effect Effects 0.000 description 1
- 238000012250 transgenic expression Methods 0.000 description 1
- 230000014621 translational initiation Effects 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- 101150081616 trpB gene Proteins 0.000 description 1
- 101150111232 trpB-1 gene Proteins 0.000 description 1
- 230000002485 urinary effect Effects 0.000 description 1
- 210000001635 urinary tract Anatomy 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
- 230000003442 weekly effect Effects 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2239/00—Indexing codes associated with cellular immunotherapy of group A61K39/46
- A61K2239/31—Indexing codes associated with cellular immunotherapy of group A61K39/46 characterized by the route of administration
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2239/00—Indexing codes associated with cellular immunotherapy of group A61K39/46
- A61K2239/38—Indexing codes associated with cellular immunotherapy of group A61K39/46 characterised by the dose, timing or administration schedule
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
- A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
- A61K35/14—Blood; Artificial blood
- A61K35/17—Lymphocytes; B-cells; T-cells; Natural killer cells; Interferon-activated or cytokine-activated lymphocytes
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/177—Receptors; Cell surface antigens; Cell surface determinants
- A61K38/178—Lectin superfamily, e.g. selectins
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/46—Cellular immunotherapy
- A61K39/461—Cellular immunotherapy characterised by the cell type used
- A61K39/4611—T-cells, e.g. tumor infiltrating lymphocytes [TIL], lymphokine-activated killer cells [LAK] or regulatory T cells [Treg]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/46—Cellular immunotherapy
- A61K39/461—Cellular immunotherapy characterised by the cell type used
- A61K39/4613—Natural-killer cells [NK or NK-T]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/46—Cellular immunotherapy
- A61K39/463—Cellular immunotherapy characterised by recombinant expression
- A61K39/4631—Chimeric Antigen Receptors [CAR]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/46—Cellular immunotherapy
- A61K39/464—Cellular immunotherapy characterised by the antigen targeted or presented
- A61K39/4643—Vertebrate antigens
- A61K39/4644—Cancer antigens
- A61K39/464402—Receptors, cell surface antigens or cell surface determinants
- A61K39/464411—Immunoglobulin superfamily
- A61K39/464412—CD19 or B4
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
- C07K16/2803—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
- C07K16/2803—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
- C07K16/2809—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily against the T-cell receptor (TcR)-CD3 complex
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
- C07K16/2803—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
- C07K16/2818—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily against CD28 or CD152
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
- C07K16/2878—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the NGF-receptor/TNF-receptor superfamily, e.g. CD27, CD30, CD40, CD95
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
- C07K16/30—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants from tumour cells
- C07K16/3076—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants from tumour cells against structure-related tumour-associated moieties
- C07K16/3084—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants from tumour cells against structure-related tumour-associated moieties against tumour-associated gangliosides
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N5/00—Undifferentiated human, animal or plant cells, e.g. cell lines; Tissues; Cultivation or maintenance thereof; Culture media therefor
- C12N5/06—Animal cells or tissues; Human cells or tissues
- C12N5/0602—Vertebrate cells
- C12N5/0634—Cells from the blood or the immune system
- C12N5/0646—Natural killers cells [NK], NKT cells
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N5/00—Undifferentiated human, animal or plant cells, e.g. cell lines; Tissues; Cultivation or maintenance thereof; Culture media therefor
- C12N5/10—Cells modified by introduction of foreign genetic material
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
- A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
- A61K2035/124—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells the cells being hematopoietic, bone marrow derived or blood cells
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/60—Immunoglobulins specific features characterized by non-natural combinations of immunoglobulin fragments
- C07K2317/62—Immunoglobulins specific features characterized by non-natural combinations of immunoglobulin fragments comprising only variable region components
- C07K2317/622—Single chain antibody (scFv)
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2319/00—Fusion polypeptide
- C07K2319/01—Fusion polypeptide containing a localisation/targetting motif
- C07K2319/03—Fusion polypeptide containing a localisation/targetting motif containing a transmembrane segment
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2319/00—Fusion polypeptide
- C07K2319/33—Fusion polypeptide fusions for targeting to specific cell types, e.g. tissue specific targeting, targeting of a bacterial subspecies
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N2501/00—Active agents used in cell culture processes, e.g. differentation
- C12N2501/50—Cell markers; Cell surface determinants
- C12N2501/599—Cell markers; Cell surface determinants with CD designations not provided for elsewhere
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N2510/00—Genetically modified cells
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Immunology (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Organic Chemistry (AREA)
- Cell Biology (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Engineering & Computer Science (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Genetics & Genomics (AREA)
- Microbiology (AREA)
- Biomedical Technology (AREA)
- Zoology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Mycology (AREA)
- Biotechnology (AREA)
- Biochemistry (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Wood Science & Technology (AREA)
- Biophysics (AREA)
- Molecular Biology (AREA)
- Hematology (AREA)
- General Engineering & Computer Science (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Virology (AREA)
- Developmental Biology & Embryology (AREA)
- Gastroenterology & Hepatology (AREA)
- Oncology (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
- Micro-Organisms Or Cultivation Processes Thereof (AREA)
- Peptides Or Proteins (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
Description
本発明は国立衛生研究所によって授与されたRO1CA116548及びP50CA126752のもとで政府の支援によって行われた。政府は本発明に特定の権利を有する。
本開示の実施形態は、細胞生物学、分子生物学、免疫学、及び少なくとも癌医学を含む医学の少なくとも分野を包含する。
本開示は、NKT細胞が十分なレベルまで増殖し、生体内にて十分なレベルで持続して治療効果を達成することができるので免疫療法での使用に好適なNKT細胞を提供する。本開示のNKT細胞は、少なくともある程度それらが高い治療適用性を有するようにするCD62Lを発現し、その発現を維持するように操作される。NKT細胞におけるCD62Lの発現のそのような維持は、1以上の共刺激作用因子への曝露の際を含む同時刺激の際に少なくともある程度生じる。
特定の実施形態では、NKT細胞は、細胞がCD62Lの発現を維持できるようにする1以上の共刺激作用因子への曝露に続いて向上した試験官内の増殖及び生体内での存続性を有するので、NKT細胞は治療応用で有用である。1以上の共刺激作用因子は任意の種類のものでもよいが、具体的な実施形態では、それらは、1以上のサイトカイン;(b)共刺激受容体を標的とする1以上のアゴニスト抗体を含む基材(たとえば、ビーズ、プレート等);及び/または(c)CD1dの発現を含み、且つ1以上の共刺激受容体の1以上のリガンドの発現を含む抗原提示細胞のような細胞を含む。NKT細胞がサイトカインに曝露される場合では、サイトカインは好適な種類のものであってもよいが、具体的な場合では、サイトカインはIL-21、IL-2、IL-7、IL-15、IL-12、IL-18、TNFアルファまたはそれらの組み合わせである。具体的な実施形態では、CD62L+NKT細胞はIL-2の存在下での培養の際、IL-21を発現し、IL-21はCD62Lの発現を保持する。
特定の実施形態では、それを必要とする個体への送達に先立ってNKT細胞は遺伝子操作される。NKT細胞は普通、TCR刺激及び同時刺激の後に操作され;特定の実施形態では、遺伝子操作は刺激後1、2、3、4、5日以上以内に発生する(且つこれは、使用される形質導入の種類に左右されてもよく;たとえば、レトロウイルスベクターではそれは2日以内である)。
本開示の細胞は、1以上の共刺激作用因子によって同時刺激されているCD62L陽性NKT細胞と同様にそれ自体抗原提示細胞である特定の共刺激作用因子(抗原提示細胞活性を有する非天然の細胞と呼ばれてもよい)の双方を含む。一部の実施形態では、CD1dを発現している非天然の細胞であり、且つ1以上の共刺激受容体の1以上のリガンドを発現している人工的な抗原提示細胞である、物質の組成物がある。
本開示はまた、本明細書で定義されているような抗原特異的なCARをコードする核酸配列を含む組成物及び該核酸配列を抱えている細胞も包含する。核酸配列は特定の態様では組換え核酸配列であり、合成であってもよい。それはPNA(ペプチド核酸)と同様にDNA、RNAを含んでもよく、それはそれらのハイブリッドであってもよい。
本開示によれば、用語「医薬組成物」は個体に投与するための組成物を指す。本開示の特定の態様では、医薬組成物は複数のNKT細胞を含む。好まれる実施形態では、医薬組成物は、非経口、経皮、腔内、動脈内、クモ膜下もしくは静脈内の投与、または癌への直接注入のための組成物を含む。前記医薬組成物は点滴または注射を介して個体に投与されることが特に想定される。好適な組成物の投与は、様々な方法によって、たとえば、静脈内、皮下、腹腔内、筋肉内、局所または皮内の投与によって達成されてもよい。
実例として、癌患者または癌に感受性の患者または癌を有することが疑われる患者は本明細書に記載されているように治療されてもよい。本明細書に記載されているように操作されたNKT細胞を個体に投与し、長期間保持してもよい。個体は1回以上の細胞の投与を受けてもよい。一部の実施形態では、遺伝子操作された細胞を被包して免疫認識を阻害し、腫瘍の部位に配置する。
本明細書に記載されている組成物のいずれかがキットに含まれてもよい。非限定例では、細胞または細胞を操作する試薬がキットに含まれてもよい。特定の実施形態では、NKT細胞またはNKT細胞を含む細胞の集団がキットに含まれてもよい。そのようなキットは細胞の操作用の1以上の試薬を有してもよいし、または有さなくてもよい。そのような試薬には、たとえば、小分子、タンパク質、核酸、抗体、緩衝液、プライマー、ヌクレオチド、塩及び/またはそれらの組み合わせが挙げられる。1以上のサイトカインをコードするヌクレオチドまたはサイトカイン自体がキットに含まれてもよい。サイトカインまたはアゴニストモノクローナル抗体を含む抗体のようなタンパク質がキットに含まれてもよい。抗体を含む基材または裸の基材自体がキットに含まれてもよく、一部の実施形態では、抗体保有の基材を生成する試薬がキットに含まれる。基材はビーズまたはプレートを含む任意の種類のものであってもよい。抗原提示細胞活性を含む細胞またはそれを生成する試薬がキットに含まれてもよい。それを生成する試薬を含む、キメラ抗原受容体またはT細胞受容体をコードするヌクレオチドがキットに含まれてもよい。
実施例1
生体内の存続性に関与するNKT細胞サブセットの特定及び治療活性及び培養でのこのサブセットの増殖に必要とされる条件を定義すること
実施例2
CD62L+NKT細胞は優れた生体内での存続性及び抗腫瘍活性を有する
実施例3
方法及び材料の実施例
Daudi、Raji、DAOY、Ramos及び293Tの細胞はATCCから購入した。Daudi、Raji、及びRamosの細胞はRPMIで培養したのに対してDAOY及び293Tの細胞はIMDM(Invitrogen)で維持した。双方の種類の培地は10%FBS(Hyclone)、2mMのGlutaMAX-1(Gibco-BRL)によって補完した。
臍帯血のNKT細胞を分析するために、MD Anderson癌センター及びBaylor College of Medicineの施設内倫理委員会によって認可されたプロトコールに従って、MD Anderson癌センター臍帯血バンクから得た廃棄される臍帯血単位を使用した。健常ドナー(少なくとも18歳)のPBMCは、Gulf Coast地域血液センターから購入したバフィーコートから勾配遠心分離によって単離した。NKTは抗iNKTマイクロビーズ(Miltenyi Biotec)によって精製した。陰性PBMC分画を放射線照射(40Gy)して、等分した。100ng/mLのαGalCer(Kyowa Hakko Kirin)でパルスした自己PBMCのアリコートによってNKTを刺激した。組換えIL-2(200U/ml,National Cancer Institute Frederick)を隔日で完全RPMI(HyClone RPMI1640,10%の熱非働化ウシ胎児血清及び2mMのGlutamax)に添加した。NKTを10日間増殖させ、次いで自己PBMC(40Gyで照射した)または指示した場合APCとしてのRamos細胞(100Gyで照射した)によって再刺激した。再刺激の3日後、24穴の非組織培養プレートをレトロネクチン(Takara Bio)で被覆し、洗浄後、CAR.CD19を含有する1mlのレトロウイルス上清によって植菌し、4600Gで60分間遠心した。次いで、ウイルス上清を取り除き、刺激したNKTを完全培地及び200U/mlのrhIL-2でのウェルに加えた。48時間後、細胞をプレートから取り出し、洗浄し、106個/mlの濃度で200U/mlのIL-2を伴った完全RPMIに再浮遊させ、連続した増殖のためにプレートに播いた。トリパンブルー(Life technologies)計数によってNKT細胞の数を決定した。指示された場合、NKTまたはCAR-NKTをCD62L-PEmAb(GREG-56,BD Biosciences)と抗PEマイクロビーズ(Miltenyi)によって標識し、その後、製造元の指示書に従ってCD62L+及びCD62L-のサブセットに磁気で選別した。選別した細胞の表現型をFACSによって決定した。
CAR.CD19及びCAR.GD2の構築物は、以前記載された(Heczeyら,2014;Puleら,2005)ように作製され、それらは、IgG1のヒンジ領域に由来する短いスペーサーを介してCD8αに由来する膜貫通ドメインに接続されたCD19に特異的な抗体FMC-63またはGD2に特異的な抗体14G2aに由来するscFvとその後のζ鎖に融合された4-1BBのシグナル伝達細胞内ドメイン配列を含有した。レトロウイルス上清は、キメラ抗原を含有するプラスミドの組み合わせによる293T細胞の形質移入によって産生されたが、以前記載された(Veraら,2006)ようにRDFプラスミドはRD114のエンベロープをコードし、PegPam3プラスミドはMoMLVのgag-polをコードした。
NKTをCFSE(Invitrogen)で標識し、αGalCerでパルスしたPBMCによって、または20ng/mlの抗CD3(OKT3)を単独で、もしくは0.5μg/mlの抗CD28(CD28.2)及び/または1.5μg/mlの抗4-1BB(h41BB-M127)(BD Biosciences)との組み合わせで被覆したプレートによって刺激した。フローサイトメトリーを用いてCFSEの希釈を測定することによって3日目及び6日目に細胞増殖を調べた。加えて、アネキシン-V及び7-AAD(BD Biosciences)による染色とその後のフローサイトメトリーによって3日目に早期及び後期段階のアポトーシスを測定した。
APCまたはアゴニスト抗体被覆のプレート(クローン6B11、BD Biosciences)によってNKTを24時間刺激した。上清を回収し、製造元の指示書に従ってLuminex(登録商標)アッセイを用いてヒトサイトカイン/ケモカインアッセイキット(Millipore)によって解析した。
以下に対する以下のmAb:HLA-C EMR8-5、CD1d CD1d42、CD86 2331、4-1BBL C65-485、OX40L ik-1、CD3 OKT、Vα24-Jα18 6B11、CD4 SK3、CD62L DREG-56、CD134 ACT35、CD137 4B4-1、PD-1 EH12.1、GATA3 L50-823(BD Biosciences)、LAG-3ポリクローナル、TIM-3 344823(R&D System)、及びウサギ抗LEF1 EP2030YmAb(ABCAM)を用いて免疫表現型検査を行った。BDまたはR&Dが提案した蛍光色素及びアイソタイプが一致したAbを陰性対照として用いた。NKT上でのCAR.CD19の発現は、抗Id(クローン136.20.1)CD19-CAR特異的なmAb(Torikaiら、2013)及びヤギ抗マウスIgG(BD Biosciences)を用いて測定した。BD FACSDivaソフトウエアv.6.0及びFlowJo7.2.5(Tree Star)を用いたLSR-II5レーザーフローサイトメトリー(BD Biosciences)で解析を行った。
以前記載された(Liuら、2013)ように4時間のルシフェラーゼアッセイを用いて親NKT及びCAR.CD19 NKTのDAOYまたはRaji細胞に対する細胞傷害性を評価した。
TRIzol試薬(Qiagen)を用いて全RNAを回収した。nCounter解析システムを用いたBCMゲノム及びRNAプロファイリングコアにて免疫学パネルv.2(NanoString)を用いて遺伝子発現の解析を行った。nSolver2.0ソフトウエア(NanoString)を用いてデータを解析した。
NSGマウスのコロニーは元々Jackson Laboratoryから入手し、BCM動物管理施設で維持されていた。ルシフェラーゼを形質導入したRajiリンパ腫細胞を2×105個i.v.注射することによって腫瘍の増殖を開始させた。3日目に4~8×106個のCAR-NKTで処理し、その後、3日ごとにIL-2(1000U/マウス)のi.p.注射を行った。生物発光画像法(Small Animal Imaging Core facility,Texas Children’s Hospital)によって週に2回腫瘍増殖を評価した。生体内での存続性の実験については、レトロウイルス構築物を用いてCAR.CD19とルシフェラーゼをNKTに同時形質導入し、それを腫瘍のないマウスまたは担腫瘍マウスにi.v.注射し、生物発光画像法を用いて週2回モニターした。動物実験はIACUCが認可したプロトコールに従って実施した。
試験管内及び生体内の実験については、本発明者らは、対応のある両側t検定を用いて2群の連続変数を評価し、Bonferroniの事後検定と共に一元配置ANOVAを用いて2を超える群の連続変数を評価した。Kaplan/Meier法及びログランク(Mantel-Cox)検定によって生存を解析して群の対を比較した。GraphPad(商標)Prism5.0(GraphPadソフトウエア)を用いて統計データを計算した。p値が0.05未満であれば、差異を有意と見なした。
MD Anderson癌センター(H-16320)及びBaylor College of Medicine(H-20911)における施設内倫理委員会によって認可されたプロトコールに従ってMD Anderson癌センター臍帯血バンクから臍帯血単位を得た。プロトコールH-16320に加わるのに先立って参加女性すべてから文書でのインフォームドコンセントを受け取った。臨床使用に好適ではない(普通少ない細胞数のために)臍帯血単位は廃棄したか、またはBaylor College of MedicineにおけるプロトコールH-20911のもとでの研究目的に使用した。動物実験は、Baylor College of Medicineの施設内動物管理委員会によって認可されたプロトコールAN-5194に従って実施した。
実施例4
NKT細胞に対するIL-21の効果
参考文献
Ara,T,ら. Critical role of STAT3 in IL-6-mediated drug resistance in human neuroblastoma.Cancer Res.2013;73(13):3S52-3S64
Baev,DV,ら.Distinct homeostatic requirements of CD4+ and CD4- subsets of Valpha24-invariant natural killer T cells in humans.Blood,2004;104(13):4150-4156.
Barakonyi,A,ら.Cutting edge:engagement of CD160 by its HLA-C physiological ligand triggers a unique cytokine profile secretion in the cytotoxic peripheral blood NK cell subset.J.lmmunol.2004;173(9):5349-5354.
Bendelac,A,Lantz,0,Quimby,ME,Yewdell,JW,Bennink,JR,Brutkiewicz,RR.CD1 recognition by mouse NK1+ T lymphocytes.Science,1995;268(5212):863-865.
Brentjens,RJら.CD19-targeted T cells rapidly induce molecular remissions in adults with chemotherapy-refractory acute lymphoblastic leukemia.Sci. Transi.Med.013;5(177):177ra13S.
Cariani,Eら.Immunological and molecular correlates of disease recurrence after liver resection for hepatocellular carcinoma.PLoS.One.2012;7(3):e32493.
Carr,T,Krishnamoorthy,V,Yu,S,Xue,HH,Kee,BL,Verykokakis,M.The transcription factor lymphoid enhancer factor 1 controls invariant natural killer T cell expansion and Th2-type effector differentiation.J.Exp.Med.2015;212(5):793-807.
Casorati,G,de LC,Dellabona,P.Invariant natural killer T cells reconstitution and the control of leukemia relapse in pediatric haploidentical hematopoietic stem cell transplantation. Oncoimmunology.2012;1(3):355-357.
Chan,WKら. Chimeric antigen receptor-redirected CD45RA-negative T cells have potent antileukemia and pathogen memory response without graft- versus-host activity.Leukemia,2015;29(2):387-395.
Cohen,NRら. Shared and distinct transcriptional programs underlie the hybrid nature of iNKT cells.Nat.Immunol.2013;14(1):90-99.
Constantinides,MG,Bendelac,A.Transcriptional regulation of the NKT cell lineage. Curr. Opin.lmmunol.2013;25(2):161-167.
Constantinides,MG,Picard,D,Savage,AK,Bendelac,A.A naive-like population of human CD1d-restricted T cells expressing intermediate levels of promyelocytic leukemia zinc finger.J.Immunol.2011;187(1):309-315.
Croft,M.Control of immunity by the TNFR-related molecule OX40(CD134).Annu.Rev.Immunol.2010;28:57-78.
D’Andrea,Aら.Neonatal invariant Valpha24+ NKT lymphocytes are activated memory cells.Eur.J.Immunol.2000;30(6):1544-1550.
de LC,ら.Invariant NKT cell reconstitution in pediatric leukemia patients given HLA-haploidentical stem cell transplantation defines distinct CD4+ and CD4- subset dynamics and correlates with remission state.J.Immunol.2011;186(7):4490-4499.
DelaRosa,Oら.Valpha24+ NKT cells are decreased in elderly humans.Exp.Gerontol.2002;37(2-3):213-217.
Der Vliet,HJら.Human natural killer T cells acquire a memory-activated phenotype before birth.Blood,2000;95(7):2440-2442.
Dhodapkar,MVら.A Reversible Defect in Natural Killer T Cell Function Characterizes the Progression of Premalignant to Malignant Multiple Myeloma.J.Exp.Med.2003;197(12):1667-76.
Dhodapkar,MV.Harnessing human CD1d restricted T cells for tumor immunity:progress and challenges.Front Biosci.2009;14:796-807.
Dotti,G,Gottschalk,S,Savoldo,8,Brenner,MK.Design and development of therapies using chimeric antigen receptor-expressing T cells.Immunol.Rev.2014;257(1):107-126.
Eger,KA,Sundrud,MS,Motsinger,AA,Tseng,M,Van,KL,Unutmaz,D.Human natural killer T cells are heterogeneous in their capacity to reprogram their effector functions.PLoS.One.2006;1:e50.
ExleyMA,Nakayama,T.NKT-cell-based immunotherapies in clinical trials.Clin.Immunol.2011;140(2):117-118.
Exley,MAら.Selective activation, expansion, and monitoring of human iNKT cells with a monoclonal antibody specific for the TCR alpha-chain CDR3 loop.Eur.J.Immunol.2008;38(6):1756-1766.
Gapin,L,Matsuda,JL,Surh,CD,Kronenberg,M.NKT cells derive from double-positive thymocytes that are positively selected by CD1d.Nat.lmmunol.2001;2(10):971-978.
Gattinoni,Lら.Acquisition of full effector function in vitro paradoxically impairs the in vivo antitumor efficacy of adoptively transferred CDS+ T cells.J.Ciin.lnvest.2005;115(6):1616-1626.
Graef,Pら.Serial transfer of single-cell-derived immunocompetence reveals sternness of CDS(+)central memory T cells.Immunity.2014;41(1):116-126.
Grupp,SAら.Chimeric antigen receptor-modified T cells for acute lymphoid leukemia.N.Engi.J.Med.2013;36S(16):1509-151S.
Heczey,Aら.Invariant NKT cells with chimeric antigen receptor provide a novel platform for safe and effective cancer immunotherapy.Blood.2014;124(18):2824-2833.
Jena,Bら.Chimeric antigen receptor (CAR)- specific monoclonal antibody to detect CD19-specific T cells in clinical trials.PLoS.One.2013;8(3):e57838.
Kalas,M,June,CH.Adoptive T cell transfer for cancer immunotherapy in the era of synthetic biology.Immunity,2013;39(1):49-60.
Kim,EY,Lynch,L,Brennan,PJ,Cohen,NR,Brenner,MB.The transcriptional programs of iNKT cells.Semin.Immunol.2015;27(1):26-32.
King,MAら.Human peripheral blood leucocyte non-obese diabetic- severe combined immunodeficiency interleukin-2 receptor gamma chain gene mouse model of xenogeneic graft-versus-host-like disease and the role of host major histocompatibility complex.Clin.Exp.Immunol.2009;157(1):104-118.
Klebanoff,CAら.Central memory self/tumor-reactive CDS+ T cells confer superior antitumor immunity compared with effector memory T cells.Proc.Nati.Acad.Sci.U.S.A,2005;102(27):9571-9576.
Kochenderfer,JNら.B-cell depletion and remissions of malignancy along with cytokine-associated toxicity in a clinical trial of anti-CD19 chimeric-antigen-receptor-transduced T cells.Blood,2012;119(12):2709-2720.
Kroczek,RA,Mages,HW,Hutloff,A.Emerging paradigms ofT-cell co-stimulation.Curr.Opin.lmmunol.2004;16(3):321-327.
Kronenberg,M,Gapin,L.The unconventional lifestyle of NKT cells.Nat.Rev.Immunol.2002;2(8):557-568.
Lantz,0,Bendelac,A.An invariant T cell receptor alpha chain is used by a unique subset of major histocompatibility complex class !-specific CD4+ and CD4-8- T cells in mice and humans.J.Exp.Med.1994;180(3):1097-1106.
Lee,PT,Benlagha,K,Teyton,L,Bendelac,A.Distinct functional lineages of human V(alpha)24 natural killer T cells.J.Exp.Med.2002;195(5):637-641.
Liu,Dら. Medulloblastoma expresses CD1d and can be targeted for immunotherapy with NKT cells.Clin.lmmunol.2013;149(1):55-64.
Loza,MJ,Metelitsa,LS,Perussia,B.NKT and T cells: coordinate regulation of NK-Iike phenotype and cytokine production.Eur.J.Immunol.2002;32(12):3453-3462.
Lynch,DH.The promise of 4-1BB (CD137)-mediated immunomodulation and the immunotherapy of cancer.Immunoi.Rev.2008;222:277-286.
Matsuda,JLら.Homeostasis of V alpha 14i NKT cells.Nat.lmmunol.2002;3(10):966-974.
Maus,MVら.Ex vivo expansion of polyclonal and antigen-specific cytotoxic T lymphocytes by artificial APCs expressing ligands for the T-cell receptor,CD28 and 4-188.Nat.Biotechnol.2002;20(2):143-148.
McEwen-Smith,RM,Salio,M,Cerundolo,V.The regulatory role of invariant NKT cells in tumor immunity. Cancer Immunoi.Res.2015;3(5):425-435.
Metelitsa,LSら.Human NKT cells mediate antitumor cytotoxicity directly by recognizing target cell CD1d with bound ligand or indirectly by producing IL-2 to activate NK cells.J.Immunol.2001;167(6):3114-3122.
Metelitsa,LS.Anti-tumor potential of type I NKT cells against CD1d-positive and CD1d-negative tumors in humans.Clin.lmmunol.2011;140(2):119-129.
Metelitsa,LSら.Natural killer T cells infiltrate neuroblastomas expressing the chemokine CCL2.J.Exp.Med.2004;199(9):1213-1221.
Moiling,JWら.Low levels of circulating invariant natural killer T cells predict poor clinical outcome in patients with head and neck squamous cell carcinoma.J.Clin.Oncol.2007;25(7):862-868.
MorrisESら.NKT cell-dependent leukemia eradication following stem cell mobilization with potent G- CSF analogs.J.Ciin.lnvest.2005;115(11):3093-3103.
Motohashi,S,Okamoto,Y,Yoshino,I,Nakayama,T. Anti-tumor immune responses induced by iNKT cell-based immunotherapy for lung cancer and head and neck cancer.Clin.lmmunol.2011;140(2):167-176.
Okada,R,Kondo,T,Matsuki,F, Takata,H, Takiguchi,M.Phenotypic classification of human CD4+ T cell subsets and their differentiation.Int.lmmunol.2008;20(9):1189-1199.
Pegram,HJ,Smith,EL,Rafiq,S,Brentjens,RJ.CAR therapy for hematological cancers: can success seen in the treatment of 8-cell acute lymphoblastic leukemia be applied to other hematological malignancies?Immunotherapy.2015;7(5):545-561.
Porcelli,S,Yockey,CE,Brenner,MB,Balk,SP.Analysis ofT cell antigen receptor (TCR) expression by human peripheral blood CD4-8- alpha/beta T cells demonstrates preferential use of several V beta genes and an invariant TCR alpha chain.J.Exp.Med.1993;178(1): 1-16.
Pillai,AB,George,Tl,Dutt,S,Teo,P,Strober,S. Host NKT cells can prevent graft-versus-host disease and permit graft antitumor activity after bone marrow transplantation.J. Immunol.2007;178(10):6242-6251.
Porter,DL,Levine,BL,Kalos,M,Bagg,A,June,CH.Chimeric antigen receptor-modified T cells in chronic lymphoid leukemia.N.Engi.J.Med.2011;365(S):725-733.
Pule,MA,Straathof,KC,Dotti,G,Heslop,HE,Rooney,CM,Brenner,MK.A chimeric T cell antigen receptor that augments cytokine release and supports clonal expansion of primary human T cells.Mol.Ther.2005;12(5):933-941.
Ramos,CA,Heslop,HE,Brenner,MK.CAR-T Cell Therapy for Lymphoma.Annu.Rev.Med.2015.
Redmond,WL,Ruby,CE,Weinberg,AD.The role ofOX40-mediated co-stimulation in T-cell activation and survival.Crit.Rev.Immunol.2009;29(3):187-201.
Sallusto,F,Geginat,J,Lanzavecchia,A.Central memory and effector memory T cell subsets: function, generation, and maintenance.Annu.Rev.Immunol.2004;22:745-763.
Savage,AKら.The transcription factor PLZF directs the effector program of the NKT cell lineage.Immunity.2008;29(3):391-403.
Savoldo,Bら.CD2S costimulation improves expansion and persistence of chimeric antigen receptor-modified T cells in lymphoma patients.J.Clin.lnvest.2011;121(5):1S22-1S26.
Sommermeyer,Dら.Chimeric antigen receptor-modified T cells derived from defined COB and CD4 subsets confer superior antitumor reactivity in vivo.Leukemia,2015.
Suhoski,MMら. Engineering artificial antigen-presenting cells to express a diverse array of co- stimulatory molecules.Mol.Ther.2007;15(5):981-988.
Tachibana,Tら.Increased intratumor Valpha24-positive natural killer T cells: a prognostic factor for primary colorectal carcinomas.Clin.Cancer Res.2005;11(20):7322-7327.
Tahir,SMら.Loss of IFN-gamma production by invariant NK T cells in advanced cancer.J.Immunol.2001;167(7):4046-4050.
Taniguchi,M,Harada,M,Dashtsoodol,N,Kojo,S.Discovery of NKT cells and development of NKT cell-targeted anti-tumor immunotherapy.Proc.Jpn.Acad.Ser.B.Phys.Biol.Sci.2015;91(7):292-304.
Thomas,AK,Maus,MV,Shalaby,WS,June,CH,Riley,JL.A cell-based artificial antigen-presenting cell coated with anti-CD3 and CD28 antibodies enables rapid expansion and long-term growth of CD4 T lymphocytes.Clin.lmmunol.2002;105(3):259-272.
Torikai,Hら.Toward eliminating HLA class I expression to generate universal cells from allogeneic donors.Blood,2013;122(8):1341-1349.
Uldrich,APら.NKT cell stimulation with glycolipid antigen in vivo:costimulation-dependent expansion,Bim-dependent contraction, and hyporesponsiveness to further antigenic challenge.J.Immunol.2005;175(5):3092-3101.
van den Heuvel,MJ,Garg,N,Van,KL,Haeryfar,SM.NKT cell costimulation:experimental progress and therapeutic promise.Trends Mol.Med.2011;17(2):65-77.
Vera,Jら.T lymphocytes redirected against the kappa light chain of human immunoglobulin efficiently kill mature B lymphocyte-derived malignant cells.Blood,2006;108(12):3890-3897.
Vivier,E,Ugolini,S,Blaise,D,Chabannon,C,Brossay,L. Targeting natural killer cells and natural killer Tcells in cancer.Nat.Rev.Immunol.2012;12(4):239-252.
Wang,Xら.Phenotypic and functional attributes of lentivirus -modified CD19-specific human COB+central memory T cells manufactured at clinical scale.J.lmmunother.2012;35(9):689-701.
Xu,Yら.Closely related T-memory stem cells correlate with in vivo expansion of CAR.CD19-T cells and are preserved by IL-7 and IL-15.Blood,2014;123(24):3750-3759.
Yamasaki,Kら.Induction of NKT cell-specific immune responses in cancer tissues after NKT cell-targeted adoptive immunotherapy.Clin.lmmunol.2011;138(3):255-265
Claims (29)
- 免疫療法で使用するためのナチュラルキラーT(NKT)細胞を調製する方法であって、CD62L陽性NKT細胞についてNKT細胞の集団を濃縮する工程を含む、前記方法。
- 前記CD62L陽性NKT細胞が、T細胞受容体の刺激と共刺激受容体及び/またはサイトカインの同時刺激とによって活性化される請求項1に記載の方法。
- 治療を必要とする個体に治療上有効な量の前記細胞を送達する工程をさらに含む請求項1または2に記載の方法。
- 前記細胞が、1以上のキメラ抗原受容体、T細胞受容体、1以上のサイトカイン、1以上のサイトカイン受容体、1以上のキメラサイトカイン受容体、またはそれらの組み合わせを発現するように操作される請求項1、2または3に記載の方法。
- 免疫療法を用いて病状について個体を治療する方法であって、
(a)CD62L陽性NKT細胞についてNKT細胞の集団を濃縮するまたはCD62L陽性NKT細胞について濃縮されているNKT細胞の集団を得る工程と、
(b)治療上有効な量の前記CD62L陽性NKT細胞を前記個体に提供する工程とを含む、前記方法。 - 免疫療法を用いて病状について個体を治療する方法であって、
CD62L+NKT細胞とCD62L-NKT細胞の集団混合物を1以上の共刺激作用因子に曝露して同時刺激されたCD62L+NKT細胞について濃縮し、CD62L+NKT細胞を作出することによって前記集団混合物からCD62L+NKT細胞を増殖させる工程と、
前記個体に治療上有効な量の前記同時刺激されたCD62L+NKT細胞を提供する工程とを含む、前記方法。 - 刺激作用因子及び共刺激作用因子が
(a)1以上のサイトカイン、
(b)T細胞受容体に対するアゴニスト抗体またはリガンド(たとえば、OKT3mAb、6B11mAb、または結合したアルファ-ガラクトシルセラミドのようなアゴニスト糖脂質を伴った組換えヒトCD1d)及び共刺激受容体を標的とする1以上のアゴニスト抗体を含む基材、または
(c)CD1dの発現を含み、且つ1以上の共刺激受容体の1以上のリガンドの発現を含む抗原提示細胞を含む請求項6に記載の方法。 - 前記CD1dの発現が結合したアゴニスト糖脂質を伴う請求項7に記載の方法。
- 前記糖脂質がアルファ-ガラクトシルセラミドである請求項8に記載の方法。
- 前記サイトカインが、IL-21、IL-2、IL-7、IL-15、IL-12、TNFアルファ及びそれらの組み合わせから成る群から選択される請求項7、8または9に記載の方法。
- 前記基材がビーズ、プレートまたはゲルである請求項7~10のいずれか1項に記載の方法。
- 前記抗原提示細胞に1以上のポリヌクレオチドが形質導入され、1以上の共刺激受容体の1以上のリガンドを発現する請求項7~11のいずれか1項に記載の方法。
- 前記共刺激受容体がCD28、OX40、4-1BB、ICOS、CD40、CD30、CD27、またはそれらの組み合わせである請求項7~12のいずれか1項に記載の方法。
- 前記共刺激受容体の前記リガンドが、CD80、CD86、OX40L、4-1BBL、ICOSリガンド、CD154、CD30L、またはそれらの組み合わせである請求項7~13のいずれか1項に記載の方法。
- 前記NKT細胞が遺伝子操作を含む請求項7~14のいずれか1項に記載の方法。
- 前記遺伝子操作が前記細胞に癌細胞ターゲティング活性を提供する請求項15に記載の方法。
- 前記癌細胞ターゲティング活性が癌細胞上の抗原のターゲティングを含む請求項16に記載の方法。
- 前記遺伝子操作がT細胞受容体を含む請求項15~17のいずれか1項に記載の方法。
- 前記遺伝子操作がキメラ抗原受容体を含む請求項15~17のいずれか1項に記載の方法。
- 1以上の共刺激作用因子に前記集団を曝露した後、前記NKT細胞が遺伝子操作される請求項15~19のいずれか1項に記載の方法。
- 1以上の共刺激作用因子に前記集団を曝露した後1、2、3、4、5、6日以上以内に、前記NKT細胞が遺伝子操作される請求項20に記載の方法。
- 免疫療法のためのNKT細胞を作出する方法であって、NKT細胞の集団を同時刺激して前記NKT細胞の少なくとも一部でCD62Lの発現を維持する工程を含む、前記方法。
- さらに、それを必要とする個体に有効な量の前記NKT細胞を提供する工程を含む請求項22に記載の方法。
- 免疫療法のためのNKT細胞を作出する方法であって、CD62L+NKT細胞の集団を目的があって濃縮するまたは保持するように設計された1以上の共刺激作用因子にCD62L+NKT細胞の事前に選別された集団またはCD62L+NKT細胞とCD62L-NKT細胞との混合集団を曝露する工程を含む、前記方法。
- さらに、前記混合集団を得る工程を含む請求項24に記載の方法。
- 前記混合集団が、前記濃縮された集団が送達されるであろう個体に由来する請求項24または25に記載の方法。
- 前記混合集団が、前記濃縮された集団が送達されるであろう前記個体とは異なる個体に由来する請求項24または25に記載の方法。
- 前記混合集団が寄託物に由来する請求項24または25に記載の方法。
- 前記混合集団が商業的に得られる請求項24または25に記載の方法。
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2024049466A JP2024073656A (ja) | 2015-04-23 | 2024-03-26 | 生体内での存続性及び治療活性及びその増殖のためのnkt細胞サブセット |
Applications Claiming Priority (6)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201562151690P | 2015-04-23 | 2015-04-23 | |
US62/151,690 | 2015-04-23 | ||
US201662309525P | 2016-03-17 | 2016-03-17 | |
US62/309,525 | 2016-03-17 | ||
PCT/US2016/028693 WO2016172372A1 (en) | 2015-04-23 | 2016-04-21 | Nkt-cell subset for in vivo persistence and therapeutic activity and ppropagation of same |
JP2017555308A JP7086375B2 (ja) | 2015-04-23 | 2016-04-21 | 生体内での存続性及び治療活性及びその増殖のためのnkt細胞サブセット |
Related Parent Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2017555308A Division JP7086375B2 (ja) | 2015-04-23 | 2016-04-21 | 生体内での存続性及び治療活性及びその増殖のためのnkt細胞サブセット |
Related Child Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2024049466A Division JP2024073656A (ja) | 2015-04-23 | 2024-03-26 | 生体内での存続性及び治療活性及びその増殖のためのnkt細胞サブセット |
Publications (2)
Publication Number | Publication Date |
---|---|
JP2022058482A true JP2022058482A (ja) | 2022-04-12 |
JP2022058482A5 JP2022058482A5 (ja) | 2023-09-11 |
Family
ID=57143558
Family Applications (3)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2017555308A Active JP7086375B2 (ja) | 2015-04-23 | 2016-04-21 | 生体内での存続性及び治療活性及びその増殖のためのnkt細胞サブセット |
JP2022000207A Pending JP2022058482A (ja) | 2015-04-23 | 2022-01-04 | 生体内での存続性及び治療活性及びその増殖のためのnkt細胞サブセット |
JP2024049466A Pending JP2024073656A (ja) | 2015-04-23 | 2024-03-26 | 生体内での存続性及び治療活性及びその増殖のためのnkt細胞サブセット |
Family Applications Before (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2017555308A Active JP7086375B2 (ja) | 2015-04-23 | 2016-04-21 | 生体内での存続性及び治療活性及びその増殖のためのnkt細胞サブセット |
Family Applications After (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2024049466A Pending JP2024073656A (ja) | 2015-04-23 | 2024-03-26 | 生体内での存続性及び治療活性及びその増殖のためのnkt細胞サブセット |
Country Status (10)
Country | Link |
---|---|
US (3) | US12048716B2 (ja) |
EP (1) | EP3291835B1 (ja) |
JP (3) | JP7086375B2 (ja) |
KR (1) | KR20180021683A (ja) |
CN (2) | CN107847585B (ja) |
AU (2) | AU2016250598A1 (ja) |
CA (1) | CA2983434A1 (ja) |
HK (1) | HK1252164A1 (ja) |
SG (1) | SG11201708600RA (ja) |
WO (1) | WO2016172372A1 (ja) |
Families Citing this family (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN106434556B (zh) * | 2016-11-22 | 2019-10-11 | 上海新长安生物科技有限公司 | 一种体外诱导扩增i型nkt细胞的方法 |
EP3441461A1 (en) * | 2017-08-11 | 2019-02-13 | Baylor College of Medicine | Cd1d-restricted nkt cells as a platform for off-the-shelf cancer immunotherapy |
WO2019067951A2 (en) * | 2017-09-29 | 2019-04-04 | Nantcell, Inc. | CD1D AND TCR-NKT CELLS |
CN112584844A (zh) * | 2018-05-31 | 2021-03-30 | 华盛顿大学 | 用于治疗血液系统恶性肿瘤的基因组编辑的恒定自然杀伤t(inkt)细胞 |
CN109402053A (zh) * | 2018-10-17 | 2019-03-01 | 广州元帅生物科技有限公司 | 一种外周血来源单个核细胞的分离及诱导培养方法 |
EP4011389A4 (en) * | 2019-08-09 | 2024-09-04 | Riken | COMBINED USE OF ARTIFICIAL ADJUVANT VECTOR CELLS AND IMMUNOSTIMULANT |
US20220249562A1 (en) * | 2019-08-21 | 2022-08-11 | Akeso Therapeutics, Inc. | Type iii nkt cells and related compositions and methods |
EP4055150A4 (en) * | 2019-11-06 | 2023-12-06 | Baylor College Of Medicine | METHOD FOR PRODUCING CYTOTOXIC EFFECTOR MEMORY T CELLS FOR T CELL TREATMENT OF CANCER |
US11591381B2 (en) | 2020-11-30 | 2023-02-28 | Crispr Therapeutics Ag | Gene-edited natural killer cells |
Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20130309213A1 (en) * | 2010-05-12 | 2013-11-21 | Virginia Commonwealth University | Composition and method for immunological treatment of cancer, prevention of cancer recurrence and metastasis, and overcoming immune suppresor cells |
US20140255363A1 (en) * | 2011-09-16 | 2014-09-11 | Baylor College Of Medicine | Targeting the tumor microenvironment using manipulated nkt cells |
WO2014138315A1 (en) * | 2013-03-05 | 2014-09-12 | Baylor College Of Medicine | Heparanase expression in human t lymphocytes |
US20150086584A1 (en) * | 2012-03-22 | 2015-03-26 | University Of Miami | Multi-specific binding agents |
WO2015051247A1 (en) * | 2013-10-03 | 2015-04-09 | University Of Maryland, Baltimore | Nanoparticle based artificial antigen presenting cell mediated activation of nkt cells |
Family Cites Families (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB9304200D0 (en) | 1993-03-02 | 1993-04-21 | Sandoz Ltd | Improvements in or relating to organic compounds |
ES2382775T3 (es) | 2004-10-08 | 2012-06-13 | Government Of The United States Of America,As Represented By The Secretary, Department Of Health And Human Services | Inmunoterapia adoptiva con supervivencia de linfocitos T potenciada. |
AU2010337829B2 (en) | 2009-12-29 | 2015-03-19 | Gamida-Cell Ltd. | Methods for enhancing natural killer cell proliferation and activity |
US9089520B2 (en) | 2010-05-21 | 2015-07-28 | Baylor College Of Medicine | Methods for inducing selective apoptosis |
EP2614151B1 (en) | 2010-09-08 | 2019-07-24 | Chemotherapeutisches Forschungsinstitut Georg-Speyer-Haus | Interleukin 15 as selectable marker for gene transfer in lymphocytes |
CA2781954A1 (en) | 2011-06-28 | 2012-12-28 | F2M International Inc. | Hose hanger |
WO2013070468A1 (en) | 2011-11-08 | 2013-05-16 | The Trustees Of The University Of Pennsylvania | Glypican-3-specific antibody and uses thereof |
SG11201404285VA (en) | 2012-02-22 | 2014-10-30 | Univ Pennsylvania | Compositions and methods for generating a persisting population of t cells useful for the treatment of cancer |
EP3105335B1 (en) | 2014-02-14 | 2019-10-02 | Board Of Regents, The University Of Texas System | Chimeric antigen receptors and methods of making |
-
2016
- 2016-04-21 WO PCT/US2016/028693 patent/WO2016172372A1/en active Application Filing
- 2016-04-21 CN CN201680022908.XA patent/CN107847585B/zh active Active
- 2016-04-21 CN CN202211079587.0A patent/CN115747156A/zh active Pending
- 2016-04-21 CA CA2983434A patent/CA2983434A1/en active Pending
- 2016-04-21 US US15/135,453 patent/US12048716B2/en active Active
- 2016-04-21 JP JP2017555308A patent/JP7086375B2/ja active Active
- 2016-04-21 SG SG11201708600RA patent/SG11201708600RA/en unknown
- 2016-04-21 EP EP16783876.2A patent/EP3291835B1/en active Active
- 2016-04-21 KR KR1020177033858A patent/KR20180021683A/ko active IP Right Grant
- 2016-04-21 AU AU2016250598A patent/AU2016250598A1/en not_active Abandoned
-
2018
- 2018-05-23 US US15/987,724 patent/US11458168B2/en active Active
- 2018-09-07 HK HK18111557.2A patent/HK1252164A1/zh unknown
-
2019
- 2019-06-03 US US16/429,581 patent/US11266689B2/en active Active
-
2022
- 2022-01-04 JP JP2022000207A patent/JP2022058482A/ja active Pending
- 2022-03-14 AU AU2022201744A patent/AU2022201744A1/en active Pending
-
2024
- 2024-03-26 JP JP2024049466A patent/JP2024073656A/ja active Pending
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20130309213A1 (en) * | 2010-05-12 | 2013-11-21 | Virginia Commonwealth University | Composition and method for immunological treatment of cancer, prevention of cancer recurrence and metastasis, and overcoming immune suppresor cells |
US20140255363A1 (en) * | 2011-09-16 | 2014-09-11 | Baylor College Of Medicine | Targeting the tumor microenvironment using manipulated nkt cells |
US20150086584A1 (en) * | 2012-03-22 | 2015-03-26 | University Of Miami | Multi-specific binding agents |
WO2014138315A1 (en) * | 2013-03-05 | 2014-09-12 | Baylor College Of Medicine | Heparanase expression in human t lymphocytes |
WO2015051247A1 (en) * | 2013-10-03 | 2015-04-09 | University Of Maryland, Baltimore | Nanoparticle based artificial antigen presenting cell mediated activation of nkt cells |
Also Published As
Publication number | Publication date |
---|---|
WO2016172372A1 (en) | 2016-10-27 |
AU2022201744A1 (en) | 2022-04-07 |
EP3291835A1 (en) | 2018-03-14 |
JP7086375B2 (ja) | 2022-06-20 |
US12048716B2 (en) | 2024-07-30 |
JP2018516548A (ja) | 2018-06-28 |
CN107847585A (zh) | 2018-03-27 |
AU2016250598A1 (en) | 2017-11-23 |
US20200163992A1 (en) | 2020-05-28 |
KR20180021683A (ko) | 2018-03-05 |
EP3291835B1 (en) | 2024-08-28 |
US11266689B2 (en) | 2022-03-08 |
CN107847585B (zh) | 2022-09-23 |
CN115747156A (zh) | 2023-03-07 |
US20180264040A1 (en) | 2018-09-20 |
CA2983434A1 (en) | 2016-10-27 |
SG11201708600RA (en) | 2017-11-29 |
JP2024073656A (ja) | 2024-05-29 |
HK1252164A1 (zh) | 2019-05-17 |
US20160310532A1 (en) | 2016-10-27 |
US11458168B2 (en) | 2022-10-04 |
EP3291835A4 (en) | 2019-01-23 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JP7086375B2 (ja) | 生体内での存続性及び治療活性及びその増殖のためのnkt細胞サブセット | |
US11723962B2 (en) | Cell-based neoantigen vaccines and uses thereof | |
US20210290676A1 (en) | Improving the efficacy and safety of adoptive cellular therapies | |
JP7372728B2 (ja) | 改変t細胞に関する方法および組成物 | |
ES2963718T3 (es) | Capacidad presentadora de antígenos de células CAR-T potenciada mediante introducción conjunta de moléculas co-estimuladoras | |
JP2024016215A (ja) | 免疫細胞の有効性および増大を改善する方法 | |
JP2023090882A (ja) | キメラ抗原受容体を発現する改変された単球/マクロファージおよびその使用 | |
EP3259352A1 (en) | Chimeric antigen receptors and uses thereof | |
JP2017535261A (ja) | Cart細胞における遺伝子発現の改変およびその使用 | |
JP2017536812A (ja) | バイパータイト型およびトリパータイト型のシグナル伝達免疫細胞 | |
KR20150128997A (ko) | 면역치료용 조성물 및 방법 | |
JP7429882B2 (ja) | キメラ抗原受容体を発現する粘膜関連インバリアントt(mait)細胞 | |
KR20170093248A (ko) | 탄산무수화효소 ix 특이적 키메라 항원 수용체 및 이의 사용 방법 | |
US20190153109A1 (en) | Chimeric antigen receptors and uses thereof | |
KR20230084470A (ko) | 면역 세포 기능의 향상 | |
Ghaedrahmati et al. | Targeting immune checkpoints: how to use natural killer cells for fighting against solid tumors | |
AL-SULAITI | GENERATION AND CHARACTERIZATION OF" OFF-THE-SHELF" CHIMERIC ANTIGEN RECEPTOR ENGINEERED T CELLS (CAR-T) TO TARGET CANCER PATIENTS WITH HEMATOLOGICAL MALIGNANCIES | |
KR20230154851A (ko) | 확장 및 생체내 보존을 위한 조작된 nkt 세포 및 종양 세포 조절을 위한 사용 방법 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20220202 |
|
A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20220202 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20220916 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20230301 |
|
A601 | Written request for extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A601 Effective date: 20230531 |
|
A601 | Written request for extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A601 Effective date: 20230731 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20230901 |
|
A524 | Written submission of copy of amendment under article 19 pct |
Free format text: JAPANESE INTERMEDIATE CODE: A524 Effective date: 20230901 |
|
A02 | Decision of refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A02 Effective date: 20231127 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20240326 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20240411 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20240510 |
|
A911 | Transfer to examiner for re-examination before appeal (zenchi) |
Free format text: JAPANESE INTERMEDIATE CODE: A911 Effective date: 20240528 |
|
A912 | Re-examination (zenchi) completed and case transferred to appeal board |
Free format text: JAPANESE INTERMEDIATE CODE: A912 Effective date: 20240809 |